Transgenic expression of human APOL1 risk variants in podocytes induces kidney disease in mice

Nat Med. 2017 Apr;23(4):429-438. doi: 10.1038/nm.4287. Epub 2017 Feb 20.

Abstract

African Americans have a heightened risk of developing chronic and end-stage kidney disease, an association that is largely attributed to two common genetic variants, termed G1 and G2, in the APOL1 gene. Direct evidence demonstrating that these APOL1 risk alleles are pathogenic is still lacking because the APOL1 gene is present in only some primates and humans; thus it has been challenging to demonstrate experimental proof of causality of these risk alleles for renal disease. Here we generated mice with podocyte-specific inducible expression of the APOL1 reference allele (termed G0) or each of the risk-conferring alleles (G1 or G2). We show that mice with podocyte-specific expression of either APOL1 risk allele, but not of the G0 allele, develop functional (albuminuria and azotemia), structural (foot-process effacement and glomerulosclerosis) and molecular (gene-expression) changes that closely resemble human kidney disease. Disease development was cell-type specific and likely reversible, and the severity correlated with the level of expression of the risk allele. We further found that expression of the risk-variant APOL1 alleles interferes with endosomal trafficking and blocks autophagic flux, which ultimately leads to inflammatory-mediated podocyte death and glomerular scarring. In summary, this is the first demonstration that the expression of APOL1 risk alleles is causal for altered podocyte function and glomerular disease in vivo.

MeSH terms

  • Albuminuria / genetics
  • Alleles
  • Animals
  • Apolipoprotein L1
  • Apolipoproteins / genetics*
  • Autophagy / genetics
  • Azotemia / genetics
  • Blotting, Western
  • Endocytosis / genetics
  • Endosomes / metabolism
  • Fluorescent Antibody Technique
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Glomerulosclerosis, Focal Segmental / genetics
  • Glomerulosclerosis, Focal Segmental / pathology
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Kidney Glomerulus / metabolism*
  • Kidney Glomerulus / pathology
  • Kidney Glomerulus / ultrastructure
  • Lipoproteins, HDL / genetics*
  • Mice
  • Mice, Transgenic
  • Microscopy, Electron
  • Podocytes / metabolism*
  • Podocytes / ultrastructure
  • Renal Insufficiency, Chronic / genetics*
  • Renal Insufficiency, Chronic / pathology

Substances

  • APOL1 protein, human
  • Apolipoprotein L1
  • Apolipoproteins
  • Lipoproteins, HDL